US6222032B1 - Use of ylides of phosphorus as slightly nuceophilic strong bases - Google Patents

Use of ylides of phosphorus as slightly nuceophilic strong bases Download PDF

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US6222032B1
US6222032B1 US09/423,269 US42326999A US6222032B1 US 6222032 B1 US6222032 B1 US 6222032B1 US 42326999 A US42326999 A US 42326999A US 6222032 B1 US6222032 B1 US 6222032B1
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carbon atoms
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alkyl
alkoxy
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Guy Bertrand
Dennis Bigg
Jean-Bernard Cazaux
Stéphanie Goumri
Olivier Guerret
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CENTEE NATIONAL de la RECHERCHE SCIENTIFIQUE (CNRS)
Ipsen Pharma SAS
Centre National de la Recherche Scientifique CNRS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D227/00—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00
    • C07D227/02—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D227/06—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D227/08—Oxygen atoms
    • C07D227/087—One doubly-bound oxygen atom in position 2, e.g. lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/535—Organo-phosphoranes
    • C07F9/5352—Phosphoranes containing the structure P=C-
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
    • C07K1/08—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents
    • C07K1/082—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents using activating agents containing phosphorus
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F8/00—Chemical modification by after-treatment
    • C08F8/40—Introducing phosphorus atoms or phosphorus-containing groups

Definitions

  • the present invention relates to the use of phosphorus ylides as slightly nucleophilic strong bases.
  • the invention also relates to new phosphorus ylides and their preparation.
  • Phosphorus ylides were studied by Wittig in the 1950's (Johnson, A. W., 1993, Series, Editor, Ylides and Imines of phosphorus , Wiley & Wiley: New York). These molecules are quite simple and even if some are presented as colorants (U.S. Pat. No. 3,274,228), they are usually prepared to be used for Wittig's reaction (U.S. Pat. Nos. 3,681,428, 3,725,365) where their strong nucleophilic action is involved. But these compounds have never been used as bases in organic synthesis, and a fortiori as slightly nucleophilic strong bases.
  • the strong neutral organic bases known to date are essentially proton sponges (Alder, R. et al., J. Chem. Soc. Chem. Commun., 1968, 723), guanidines, phosphatranes and polyphosphazenes.
  • Guanidines constitute the class of strong organic bases most frequently used in organic synthesis. The best known are DBN (1,5-diazabicyclo [4.3.0] non-5-ene) and DBU (1,8-diazabicyclo [4.3.0] undec-5-ene). Other guanidines are also mentioned in the literature (Oediger, H. et al., Synthesis, 1972, 593; Schwesinger, R., Angew. Chem. Int. Ed. Eng., 1987, 26, 1164). These bases are used in elimination reactions or in oligomerization or polymerization processes as a reaction initiator (Oediger, H. et al., Synthesis, 1972, 593; Wöhrle, D. et al., Dyes and Pigments, 1992, 18, 91).
  • Phosphatranes are more recent compounds (Verkade, J., 1991, Phosphatranes as proton abstracting reagents , U.S. Pat. No. 5,051,533). Their basicity is much greater than that of guanidines, which extends their field of application. The drawback of such phosphines lies in the difficulty in obtaining them and their purification.
  • Alkaline bases such as BuLi, LiHMDS, NaHMDS, LDA also represent another large family of bases. They are often used with good yields to functionalize lactames, ketones or Schiff bases (Stork, G. et al., J. Org. Chem., 1976, 41, 3491; Myers, A. et al., J. Am. Chem. Soc., 1994, 116, 9361; Myers, A. et al., J. Am. Chem. Soc., 1995, 117, 8488; Yaozhong, J. et al., Synth.
  • the problem is therefore to find slightly nucleophilic strong bases, which are easy to synthesize and at a low cost, which would be susbstituted on the one hand for commonly used bases which are too nucleophilic and on the other hand for recent bases which are too expensive.
  • the invention therefore relates to the use of products of general formula I′
  • R′ 1 , R′ 2 and R′ 3 represent, independently, a lower alkoxy or amino radical of formula R′R′′N in which R′ and R′′ independently represent one of the following radicals, non-substituted or substituted (by one or more identical or different substituents): lower alkyl, lower alkoxy, cycloalkyl, lower aryl-alkyl, aryl, in which the substituent is a halogen atom or a lower alkyl, lower alkoxy, cyano, nitro or dialkylamino radical;
  • R′ 4 represents the hydrogen atom, a lower alkyl radical or lower alkoxy
  • R′ 5 represents the hydrogen atom, a lower alkyl radical, lower alkoxy or a polymeric support
  • halogen represents a fluorine, chlorine, bromine or iodine atom, preferably chlorine or bromine.
  • the expression lower alkyl represents a linear or branched alkyl radical having 1 to 6 carbon atoms and in particular an alkyl radical having 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl radicals.
  • the lower alkoxy radicals can correspond to the alkyl radicals indicated above.
  • the linear radicals there can be mentioned the methoxy, ethoxy, propyloxy, n-butyloxy or n-hexyloxy radicals.
  • the branched alkoxy radicals there can be mentioned the isopropyloxy, sec-butyloxy, isobutyloxy, ter-butyloxy, isopentyloxy, neopentyloxy or ter-pentyloxy radicals.
  • cycloalkyl includes any non-aromatic cyclic hydrocarbon fragment having 3 to 10 carbon atoms and preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • aryl designates radicals which are unsaturated, monocyclic or constituted by condensed rings, carbocyclic or heterocyclic, it being understood that the heterocyclic radicals can include one or more identical or different heteroatoms chosen from oxygen, sulphur or nitrogen.
  • Examples of such groups include the phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, isothiazolyl, diazolyl, triazolyl, thiatriazolyl, oxazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzaxozolyl, indolyl, purinyl, naphthyl, thionaphthyl, phenanthrenyl, anthracenyl, biphenyl, indenyl, quinolyl, isoquinolyl or quinolizinyl radicals.
  • the lower arylalkyl radicals designate the radicals in which the aryl and lower alkyl radicals respectively are as defined above such as for example benzyl, phenethyl or naphthylmethyl.
  • dialkylamino represents the amino radical substituted by two alkyl radicals, identical or different, as defined above, such as for example dimethylamino, (methyl)(ethyl)amino, diethylamino.
  • slightly nucleophilic means non nucleophilic with respect to other centres than protons.
  • strong base corresponds to the term commonly used by a person skilled in the art in the technical field considered.
  • the polymeric support can be, for example, of methacrylic, acrylic or styrenic type.
  • the invention relates more particularly to the use, as a slightly nucleophilic strong base, of products of general formula I′ as defined above characterized in that R′ 1 , R′ 2 and R′ 3 represent, independently, an amino radical of formula RR′N as defined above.
  • R′ 1 , R′ 2 and R′ 3 represent, independently, the dimethylamino, (methyl)(ethyl)amino or diethylamino radical.
  • the invention relates more particularly to the use, as a slightly nucleophilic strong base, of products of general formula I′as defined above characterized in that R′ 4 represents the hydrogen atom or an alkyl radical.
  • R′ 4 represents the hydrogen atom or the methyl or ethyl radical.
  • the invention also relates more particularly to the use, as a slightly nucleophilic strong base, of products of general formula I′as defined above characterized in that R′ 5 represents an alkyl radical, and preferably methyl, or a polymeric support.
  • R′ 5 represents an alkyl radical, and preferably methyl, or a polymeric support.
  • the polymeric support R′ 5 is of methacrylic type, acrylic type such as the expansine® polymer, or polystyrenic type.
  • the polymeric support of polystyrenic type is of general formula (s)
  • n i , m i and q i are integers greater than or equal to one.
  • the polymeric support of formula (s) can originate from the corresponding polymer of formula (p)
  • n, n′, m are integers greater than or equal to one and X represents a parting group.
  • X can be, for example, a halogen atom, the oxycarbonyl, oxysulphonyl or oxyboronyl radical.
  • the polymeric support R′ 5 originates from a polystyrenic polymer of general formula (p) as defined above in which X represents the chlorine atom and m is equal to 1, and more particularly Merrifield resin.
  • a more particular subject of the invention is the use of the compounds of formula I′ as defined above, as slightly nucleophilic strong bases in N-alkylation reactions such as, for example, the N-alkylation reactions of lactames, succinimides, oligopeptides and benzodiazepines.
  • a more particular subject of the invention is also the use of the products of general formula I′ as defined above as slightly nucleophilic strong bases in C-alkylation reactions such as, for example, the C-alkylation reactions of lactames, succinimides, Schiff bases and benzodiazepines.
  • a subject of the invention is also new phosphorus ylides and more particularly the products of general formula (I)
  • R 1 , R 2 and R 3 represent, independently, a lower alkoxy or amino radical of formula R′R′′N in which R′ and R′′ independently represent one of the following radicals, non-substituted or substituted (by one or more identical or different substituents): lower alkyl, lower alkoxy, cycloalkyl, lower aryl-alkyl, aryl, in which the substituent is a halogen atom or a lower alkyl, lower alkoxy, cyano, nitro or dialkylamino radical;
  • R 4 represents the hydrogen atom, a lower alkyl or lower alkoxy radical
  • R 5 represents a polymeric support.
  • R 1 , R 2 and R 3 represent, independently, an amino radical of formula RR′N as defined above.
  • R 1 , R 2 and R 3 represent, independently, the radical dimethylamino, (methyl)(ethyl)amino, diethylamino radical.
  • a more particular subject of the invention is the products of general formula I as defined above characterized in that R 4 represents the hydrogen atom.
  • a more particular subject of the invention is the products of general formula I as defined above characterized in that the polymeric support R 5 is of methacrylic type, acrylic type such as the polymer expansine®, or polystyrenic type.
  • the polymeric support of polystyrenic type is of general formula (s) as defined above.
  • a subject of the invention is also a process for the preparation of the products of general formula I as defined above, characterized in that
  • the preparation of compound (3), from compounds (1) and (2) is preferably carried out under an inert atmosphere, such as for example under an argon atmosphere, in a polar solvent such as 1,2-dichloroethane, acetonitrile, dimethoxyethane or diethoxymethane.
  • Compound (2) is in general in stoechiometric excess with respect to compound (1).
  • Y is such that Y ⁇ represents any anion known to a person skilled in the art such as, for example, halides, triflate.
  • the reaction medium is then agitated under reflux of the solvent. After the standard washing stages, compound (3) is dried under vacuum. In order to obtain product (I), product (3) thus obtained is treated, at ambient temperature, in the presence of a strong base.
  • the strong base can be for example a lithiated base such as alkyl lithium compounds, and more particularly butyllithium, a sodium or potassium hydride, an amide or an alcoholate.
  • the solvent can be chosen from pentane, ether, tetrahydrofuran, dimethoxyethane or diethoxymethane, in which solvent the strong base is stable. The mixture obtained is agitated for a few hours. Polymer (I) is washed under vacuum then dried. It can then be used directly without further purification.
  • the compound of formula (1) in which R 4 does not represent the hydrogen atom can be obtained by reacting the corresponding compound (I) in which R 4 represents the hydrogen atom, with a compound of formula R 4 X′ in which X′ represents a halogen atom and R 4 is as defined above but does not represent the hydrogen atom, at a temperature comprised between ⁇ 10 and +10° C., preferably at 0° C., in a solvent such as THF. After filtration and washing, the product thus obtained can be treated with a strong base in order to obtain the desired compound (I).
  • a subject of the invention is also, as new industrial products, and in particular as new industrial products intended for the preparation of products of formula (I), the products of formula (3) as described above.
  • the compounds of formula (1) and (2) are generally commercial products and can be obtained according to standard methods known to a person skilled in the art.
  • the compounds of formula (I′) in which R′ 5 represents the hydrogen atom, a lower alkyl or lower alkoxy radical, can be prepared according to standard methods known to a person skilled in the art (Johnson, A. W., 1993, Series, Editor, Ylides and Imines of phosphorus , Wiley & Wiley: New York).
  • the grafting rate is checked by the reactivity of the polymer obtained.
  • the solvent used for the grafting can also be dimethoxyethane.
  • NMR 13 C (CDCl 3 ): 37.95 (s, CH—CH 2 Ph); 49.95 (s, N—CH 2 Ph); 65.27 (s, CH—CH 2 Ph); 123,92-131.24 (s, CH arom ); 129.43, 131.99, 136.27, 137.94, 138.99, 140.05 (s, Cq); 167.43; 169.05 (s, CO and CN).
  • NMR 13 C (CDCl 3 ):28.14 (s, CH 3 ); 37.80 (s, C H 2 COOtBu); 50.28 (s, N—CH 2 Ph); 60.62 (s, CH); 80.70 (s, Cq(CH 3 ) 3 ); 124,01-131.38 (s, CH arom ); 129.54; 132.11; 136.20; 137.90; 140.31 (s, Cq); 167.50; 169.02; 171.30 (s, CO, CN and COO).
  • NMR 13 C (CDCl 3 ): 17.32 (s, CH 3 ); 49.82 (s, CH 2 Ph); 58.81 (s, CH); 123,94-131.30 (s, CH arom ); 130.38; 131.07; 136.39; 137.93; 140.20 (s, Cq); 167.16; 170.35 (s, CO and CN).
  • NMR 13 C (CDCl 3 ): 35.28 (s, N—CH 3 ); 38.10 (s, CH 2 Ph); 65.27 (s, CH); 122,77-131.45 (s, CH arom ); 129.16; 130.32; 138.15; 139.21; 142.15 (s, Cq); 168.01; 170.05 (s, CO and CN).
  • NMR 13 C (CDCl 3 ): 28.12 (s, CH 3 ); 35.21 (s, N—CH 3 ); 37.91 (s, CH 2 ); 60.56 (s, CH); 80.59 (s, C q (CH 3 ) 3 ); 122,83-130.36 (s, CH arom ); 131.52; 137.97; 139.40; 142.20 (s, C q ); 167.20; 169.70; 171.25 (s, CO, CN and COO).
  • NMR 13 C (CDCl 3 ): 17.43 (s, CH 3 ); 35.15 (s, N—CH 3 ); 58.90 (s, CH); 122,59-130.54 (s, CH arom ); 129.11; 129.63; 131.38; 138.13 (s, Cq); 166.85; 171.21 (s, CO and CN).
  • NMR 13 C (CDCl 3 ): 27.90; 28.06 (s, CH 3 ); 7.82 (s, CH 2 ); 50.81 (s, N—CH 2 ); 60.33 (s, CH); 80.61; 82.43 (s, Cq(CH 3 ) 3 ); 123,02-131.64 (s, CH arom ); 129.89; 130.60; 130.98; 138.08 (s, Cq); 67.39; 167.76; 170.92 (s, CO, CN and COO).
  • NMR 13 C (CDCl 3 ): 27.79 (s, CH 3 ); 37.69 (s, CH 2 Ph); 50.77 (s, N— C H 2 COOtBu); 64.72 (s, CH); 82.33 (s, Cq(CH 3 ) 3 ); 122,69-131.45 (s, CH arom ); 130.68; 131.10; 138.10; 138.91; 141.08 (s, Cq); 167.30; 167.47; 169.49 (s, CO, CN and COO).
  • NMR 13 C (CDCl 3 ): 17.16 (s, CH 3 ); 27.81 (s, CH— C H 3 ); 50.65 (s, CH 2 ); 58.46 (s, CH); 82.25 (s, Cq(CH 3 ) 3 ); 122,29-131.37 (s, CH arom ); 129.41; 130.82; 138.04; 141.18 (s, Cq); 167.04; 167.59; 170.50 (s, CO, CN and COO).
  • Examples 2a and 2b can also be implemented using a supported ylide as defined in the present invention, and more particularly with a polymer of formula (a) as defined above in which m>1.
  • NMR 13 C (CDCl 3 ): ⁇ 0.15 (s, CH 3 ); 53.71 (s, CH 2 ); 127,62-128.11 (s, Cq); 129,63-130 CH arom ); 169.50; 169.52 (s, CO and CN).
  • NMR 13 C (CDCl 3 ): 27.65 (s, CH 3 ); 51.03 (s, CH 2 —COOtBu); 51.03 (s, CH 2 —COOtBu); 55.88 (s, CH 2 ); 83.50 (s, Cq(CH 3 ) 3 ); 123,63-131.98 (s, CH arom ); 130.23; 130.64; 137.85; 140.56 (s, C ipso ); 168.30; 170.26; 170.58 (s, CO, COO and CN).
  • NMR 13 C (CDCl 3 ): 17.16 (s, CH 3 ); 27.81 (s, CH— C H 3 ); 50.65 (s, CH 2 ); 58.46 (s, CH); 82.25 (s, Cq(CH 3 ) 3 ); 122,29-131.37 (s, CH arom ); 129.41; 130.82; 138.04; 141.18 (s, Cq); 167.04; 167.59; 170.50 (s, CO, CN and COO).
  • NMR 13 C (CDCl 3 ): 20.44; 22.42 (s, CH 2 ); 27.73 (s, CH 3 ); 31.72 (s, CH 2 —CO); 49.21; 49.90 (s, CH 2 —N); 82.49 (s, C(CH 3 ) 3 ); 168.59; 172.37 (s, CO).
  • This example can also be implemented using a supported ylide as defined in the present invention, and more particularly with a polymer of formula (a) as defined above in which m>1.
  • N-t-Boc-L-Leucine and the hydrochloride of the methyl ester of L-phenylalanine are coupled beforehand in the presence of a BrOP coupling agent in order to obtain the corresponding dipeptide.
  • the monobenzylation product is obtained with a yield of 12% and the dibenzylation product is obtained with a yield of 28%. These compounds were analyzed by gas chromatography coupled with electron impact mass spectrometry.
  • Example 2c The polymer of Example 2c is washed several times in a dichloromethane/acetonitrile mixture, dried under vacuum and re-used in the N-benzylation reaction of norvalium under conditions as described in Example 3a.
  • the N-benzylated compound is recovered with a yield of 79%, a yield comparable to that obtained in Example 3a 3 .

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EP97401142A EP0881235A1 (fr) 1997-05-26 1997-05-26 Nouveaux ylures de phosphore, leur préparation et leurs utilisations notamment en tant que bases fortes faiblement nucléophiles
EP97401142 1997-05-26
PCT/FR1998/001048 WO1998054229A1 (fr) 1997-05-26 1998-05-26 Utilisation d'ylures de phosphore en tant que bases fortes faiblement nucleophiles

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US10195210B2 (en) 2010-11-08 2019-02-05 Paion Uk Ltd. Dosing regimen for sedation with CNS 7056 (Remimazolam)
US10414749B2 (en) 2013-03-04 2019-09-17 Paion Uk Limited Process for preparing 3-[(S)-7-bromo-2-((2-oxopropyl)amino)-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]propionic acid methyl ester
US10472365B2 (en) 2006-07-10 2019-11-12 Paion Uk Limited Short-acting benzodiazepine salts and their polymorphic forms

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US7160880B1 (en) 1999-05-14 2007-01-09 Cenes Limited Short-acting benzodiazepines
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FR2833602B1 (fr) * 2001-12-14 2004-03-12 Rhodia Chimie Sa Procede de preparation de polyorganosiloxanes (pos) par polycondensation/redistribution d'oligosiloxanes, en presence d'une superbase et superbases employees

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EP0986585A1 (fr) 2000-03-22
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JP2002504900A (ja) 2002-02-12
DE69812614D1 (de) 2003-04-30
NO995771L (no) 1999-11-25
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WO1998054229A1 (fr) 1998-12-03
CA2291345A1 (fr) 1998-12-03

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